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Indoor Toxicity and Fungal Inhalation Risk of Patients and Clinical Findings
Eckardt Johanning, M.D. , M.Sc. Manfred Gareis, DVM (BAFF-Kulmbach, FRG)
Wayne Gordon (MSMC, New York, USA) Occupational and Environmental Life Science
Fungal Research Group Foundation, Albany, N.Y.
Fungal Research Group Foundation 2008
Fungal Exposure: Various agents and disease outcomes
Agents: • Allergens • Ergosterol • (1-3)-ß-D-glucan • Mycotoxins • microbial volatile
organic compounds (MVOCs)
• ???
Allergy + Non-allergic • Dermatitis, • Urticaria • Rhinitis, Sinusitis • Asthma • Extrinsic allergic
alveolitis “humidifier fever”
• Organic dust toxic syndrome
• Toxic – irritant effects Fungal Research Group
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Diagnostic problems
Exposure Multiple Mixture - dose
Non-specific symptoms
Multiple disease endpoints
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-Mycotoxicosis -Hypersensitivity pneumonitis
-Bronchitis -Allergic diseases
-Dermatitis; air way infections - Irritative and non-specific symptoms
rare
frequent
irreversible
reversible
Health effects of fungi
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Patients evaluated in occupational and environmental health clinic from December 1999 to February, 2005 * Adult patients (Patients ≥ 18 years at time of visit, exposure duration ~ 2y) * Advanced environmental testing (including airborne cytotoxicity study MTT) * Completed self-administered health questionnaire. Compared to adult clinic patients (controls) without self- reported exposure to dampness/mold at home or at work.
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Database
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Demographics
38 40 42 44 46 48 50 52
Control (n =26)
Patient (n =92)
Ag
e
Age (years), 95% CI
Patient: n = 79-94; Control: n = 25-26
0 10 20 30 40 50 60 70
Smoking status
Gender (%Female) [***]
% Yes
PatientControl
Age Gender - Smoker
*** = p < 0.001
Symptom complex
0 20 40 60 80 100
Allergy, prev.
CNS [***]
Lower respiratory [***]
Upper respiratory [***]
% Yes
0 20 40 60 80
Fatigue[***]
Eyes[***]
Skin[***]
% Yes
PatientControl
Patient: n = 95; Control: n = 26
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Pulmonary function test abnormalities Patient: n = 20
0 10 20 30 40 50 60 70
Obstructive (O)
Restrictive (R)
Small airway (S-A)
Combined (R) + (S-A)
Combined (O) + (S-A)
% Yes
Patient’s IgG Antibody response and comparison with environmental sampling identification
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Patient: n = 66 - 69
0 10 20 30 40
Eurotium * IgGA.fumigatus
Aspergillus * IgGA.fumigatus
Alternaria * IgGAlternaria
% IgG MSAB Elevated
Fungi reported: YES
Fungi reported: NO
Patient’s IgG Antibody response and comparison with environmental sampling identification
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Patient: n = 66 - 69
0 10 20 30 40
Trichoderma *IgG Trichoderma
Stachybotrys *IgG Stachybotrys
Phoma * IgGPhoma
Penicillium * IgGPenicillium
% IgG MSAB Elevated
Fungi reported: YES
Fungi reported: NO
Patient’s IgE Antibody response and comparison with environmental sampling identification
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Patient: n = 63 - 67
0 2 4 6 8 10 12
Cladosporium * IgECladosporium
Chaetomium * IgEChaetomium
Aspergillus * IgEAspergillus
% IgE MSAB Elevated
Fungi reported: YESFungi reported: NO
IgE Mold Specific Antibodies & Environmental Exposure
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Patient: n = 63 - 67
0 10 20 30
Stachybotrys* IgE
Stachybotrys
Eurotium *IgE
Aspergillus
% IgE MSAB Elevated
Fungi reported: YESFungi reported: NO
IgA Mold Specific Antibodies & Stachybotrys chartarum exposure
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Patient: n = 68
0 10 20 30 40
Stachybotrys* IgA
Stachybotrys
% IgA MSAB Elevated
Fungi reported: YESFungi reported: NO
Serological Marker Sensitivity, Specificity, positive and negative predictive value
Agent – Serol-ogy
Sensitivity Specificity + predictive value
- predictive value
A. fumigatus IgE 0.04 0.91 0.93 0.85 S. chartarum IgE 0.05 0.94 0.6 0.33 Alternaria a. IgG 0.22 0.74 0.53 0.42 Penicillium n. IgG
0.25 0.77 0.95 0.08
A. fumigatus IgG 0.24 0.83 0.17 0.88 S. chartarum IgG (adults only)
0.09 0.85 0.48 0.37
S. chartarum IgG (children only)
0.07 1 1 0.26
Trichoderma v. IgG
0.28 0.65 0.22 0.71
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Airborne fungal toxicity assessment
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METHODS Indoor environments of 55 patients (1999 and 2005) with verified moisture related building damage and indoor fungal growth were studied. In total, 161 high-volume air samples were analyzed for trichothecene (Roridin A) content by the ELISA method and fungi in this comparison.
Air sampling (24 h)
Mycology with special attention to Stachybotrys ch.
Inhalation Exposure - Logistics and Methodology
Case Clinical data Bulk samples
7 Mycotoxin analyse Toxicity
Mycology
Mycotoxins
Toxicity
HPLC-DAD GC-MS EIA
Cytotoxicity screening of crude extracts (MTT-test)
paper in preparation Fungal Research Group
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Airborne Cyto-Toxicity Results: Samples
0 10 20 30 40 50 60 70
Low toxicity(IC50>125)
Moderate (31.25 <IC50 =< 125
High (IC50 =<31.25)
Tox
icity
% (n = 203)
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Airborne Cytotoxicity & Viable Fungi
RoA Elisa (ng/g) Spearman’s Viable fungi (% yes, (n))
level < 2 2 < 5 5 < 10 10 < 50 => 50 Approx. T Approx. p
Acremonium sp. (+) 4.0 (1) 4.0 (1) 4.0 (1) 0.0 (0) 0.0 (0)
-0.210 0.835 + 8.0 (2) 8.0 (2) 8.0 (2) 16.0 (4) 16.0 (4) ++ 8.0 (2) 4.0 (1) 8.0 (2) 4.0 (1) 4.0 (1) +++ 0.0 (0) 4.0 (1) 4.0 (1) 0.0 (0) 0.0 (0)
Alternaria sp. (+) 7.7 (1) no data 7.7 (1) 0.0 (0) 0.0 (0) 0.504 0.624 + 15.4 (2) no data 15.4 (2) 7.7 (1) 15.4 (2)
++ 15.4 (2) no data 0.0 (0) 0.0 (0) 15.4 (2)
Aspergillus sp. (+) 2.0 (2) 2.0 (2) 2.0 (2) 0.0 (0) 0.0 (0)
0.386 0.700 + 12.9 (13) 15.8 (16) 16.8 (17) 4.0 (4) 4.0 (4) ++ 8.9 (9) 5.9 (6) 2.0 (2) 4.0 (4) 4.0 (4) +++ 5.9 (6) 1.0 (1) 5.0 (5) 2.0 (2) 2.0 (2)
Chaetomium sp. (+) 5.9 (1) 0.0 (0) 0.0 (0)` 0.0 (0) 0.0 (0)
-2.403 0.030 + 0.0 (0) 5.9 (1) 17.6 (3) 5.9 (1) 23.5 (4) ++ 11.8 (2) 0.0 (0) 5.9 (1) 0.0 (0) 0.0 (0) +++ 11.8 (2) 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0)
Cladosporium sp.
(+) 1.4 (1) 1.4 (1) 4.1 (3) 1.4 (1) 0.0 (0)
1.599 0.114 + 23.0 (17) 18.9 (14) 17.6 (13) 6.8 (5) 2.7 (2) ++ 6.8 (5) 2.7 (2) 0.0 (0) 5.4 (4) 5.4 (4) +++ 0.0 (0) 0.0 (0) 0.0 (0) 0.0 (0) 2.7 (2)
Paecilomyces sp.
(+) 0.0 (0) 3.6 (1) 10.7 (3) 3.6 (1) 0.0 (0) -1.111 0.277 + 32.1 (0) 10.7 (3) 10.7 (3) 7.1 (2) 14.3 (4)
++ 3.6 (1) 0.0 (0) 3.6 (1) 0.0 (0) 0.0 (0)
Penicillium sp. + 10.8 (12) 14.4 (16) 10.8 (12) 9.0 (10) 4.5 (5) -1.601 0.112 ++ 14.4 (16) 4.5 (5) 5.4 (6) 4.5 (5) 2.7 (3)
+++ 9.0 (10) 2.7 (3) 2.7 (3) 2.7 (3) 3.6 (4)
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28%
56%
Cytotoxicity Testing of Filter Papers from 24 h Air Sampling
n=7 n=14
Inhalation Exposition - Results
n cases Stachybotrys chartarum Macrocyclic Trichothecenes 5 + + 5 - + 3 + - 8 - -
toxic samples
III
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Fungal toxicity and neurocognitive dysfunction
(W. Gordon, PhD et al)
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• 22 neurocognitive cases selected that included indoor air toxicity assessments
Brain Injury Screening Questionnaire (BISQ)
Results: Gorden et.al., Applied Neuropsychology 2004, Vol. 11, No.2, 65-74
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Patients with (toxigenic) indoor mold exposure history and traumatic brain injury report similar symptoms and problems
Neurocognitive Testing Results, WMS III, Airborne Toxicity Findings
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Moderate-high, n = 11; No, n = 8
80 85 90 95 100 105 110 115 120 125 130
No
Moderate
No
Moderate
No
Moderate
No
Moderate
WM
S-III
,V
isua
lIm
med
iate
Mem
ory
Inde
x
WM
S-III
,A
udito
ryIm
med
iate
Mem
ory
Inde
x
WM
S_III
,W
orki
ngM
emor
yIn
dex
WM
S-III
,G
ener
alM
emor
yIn
dex
Mean (score), 95% CI
Of 22 neurocognitive cases selected that included indoor air toxicity assessments
Neurocognitive Testing Results, WMS III, Airborne Toxicity Findings
Fungal Research Group FRGF
Moderate-high, n = 11; No, n = 8
80 85 90 95 100 105 110 115 120 125 130
No
Moderate
No
Moderate
No
Moderate
No
Moderate
WM
S-III
,A
udito
ryR
ecog
nitio
nIn
dex
WM
S-III
,V
isua
lD
elay
edM
emor
yIn
dex
WM
S-III
,A
udito
ryD
elay
edM
emor
yIn
dex
WM
S-III
,Im
med
iate
Mem
ory
Inde
x
Mean (score), 95% CI
Of 22 neurocognitive cases selected that included indoor air toxicity assessments
Neurocognitive Testing Results, WMS III, Toxicity,
% Reduced functioning (≤ 16thpercentile)
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0 10 20 30 40
WMS-III, Auditory ImmediateMemory Index (*)
WMS-III, Working Memory Index
WMS-III, General Memory Index
% Equal or below 16th percentile
Moderate to hightoxicity (n = 11)
No toxicity (n = 9)
* = p < 0.05
Of 22 neurocognitive cases selected that included indoor air toxicity assessments
Neurocognitive Testing Results, WMS III, Toxicity,
% Reduced functioning (≤ 16thpercentile)
Fungal Research Group FRGF
0 10 20 30 40 50
WMS-III, AuditoryRecognition Index
WMS-III, VisualDelayed Memory
Index
WMS-III, AuditoryDelayed Memory
Index
WMS-III,Immediate Memory
Index
WMS-III, VisualImmediate Memory
Index
% Equal or below 16th percentile
Moderate to hightoxicity (n = 11)No toxicity (n = 9)
•22 neurocognitive cases selected that included indoor air toxicity assessments
Reviews and committee papers – who are the reviewer and what are their motives?
• ACOEM – “Mold - Evidence Paper” – American College of Occupational and
Environmental Medicine (10/2002) – Authors: Hardin, Kelman, Saxon – See also: Manhattan Institute (same content) (7/03)
• IOM - Damp Indoor Spaces and Health – Institute of Medicine (2004)
• Kuopio Finland Toxic Mold Meeting (7/2004) – ISIAQ
• Norddamp (Bornehag et al, 2004)
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Critique of “evidence Papers”
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• The motives and intentions of the authors have been examined and questioned: – “A Critique of the ACOEM Statement on Mold: Undisclosed
Conflicts of Interest in the Creation of an “Evidence-based” Statement”
• By JAMES CRANER in INT J OCCUP ENVIRON HEALTH 2008;14:283–298
– “Court of Opinion: Amid Suits Over Mold. Experts Wear Two Hats; Authors of Science Paper Often Cited by Defense Also Help in Litigation”
• By David Armstrong. Wall Street Journal. (Eastern edition). New York, N.Y.: Jan 9, 2007.
– “Position paper on molds by AAAAI is seriously flawed”. • A Critique of the AAAAI Statement on Mold: The medical effects of mold exposure. by
Bush RK, Portnoy JM, Saxon A, Terr AI, Wood RA. J Allergy Clin Immunol 2006;117:326-33.
• Letters to editor of journal by different authors see: J ALLERGY CLIN IMMUNOL VOLUME 118, NUMBER 3
APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Nov. 2005, p. 7376–7388 Vol. 71, No. 11 Fungal Research Group
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Conclusions
• Patient IgE and IgG show limited correlation with specific environmental findings (low sensitivity, good specificity)
• Patient show (also) non IgE- or IGG-mediated or associated exposure effects
• New onset of symptoms and abnormalities in non-sensitized patients (new onset Dx)
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Conclusions
• Cognitive impairment symptoms similar to patients with traumatic brain injury (TBI)
• Airborne (fungal) toxicity appear to be correlated with some neurocognitive dysfunction
• Improved, specific exposure data necessary to improve environmental/occupational diagnosis
• Mycotoxin body burden indicator needed to validate study findings
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Conclusions
• Airborne Satratoxins (macrocyclic trichothecenes)
• Detection of mycotoxins in air samples not or weakly correlated with fungal spores
• S. chartarum not necessarily correlated with the presence of satratoxins
• Other cytotoxic compounds could be detected by use of the bioassay
• Methods appears to be reliable to differentiate between cytotoxic and non-cytotoxic filter papers, i.e. toxic and non-toxic environments
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“Wissen ist nicht genug – wir müssen handeln”
“Knowing is not enough; we must apply.” - J. W. Goethe
Child with asthma in Spanish Harlem, N.Y. …
Johanning et al; EHP 1999;107 (3) Fungal Research Group
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